1. Field of the Invention
This invention relates to certain alpha amino acid derivatives which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1 Hemler and Takada, European Patent Application Publication No. 330,506, published Aug. 30, 1989
2 Elices, et al., Cell, 60:577-584 (1990)
3 Springer, Nature, 346:425-434 (1990)
4 Osborn, Cell, 62:3-6 (1990)
5 Vedder, et al., Surgery, 106:509 (1989)
6 Pretolani, et al., J. Exp. Med., 180:795 (1994)
7 Abraham, et al., J. Clin. Invest., 93:776 (1994)
8 Mulligan, et al., J. Immunology, 150:2407 (1993)
9 Cybulsky, et al., Science, 251:788 (1991)
10 Li, et al., Arterioscler. Thromb., 13:197 (1993)
11 Sasseville, et al., Am. J. Path., 144:27 (1994)
12 Yang, et al., Proc. Nat. Acad. Science (USA), 90:10494 (1993)
13 Burkly, et al., Diabetes, 43:529 (1994)
14 Baron, et al., J. Clin. Invest., 93:1700 (1994)
15 Hamann, et al., J. Immunology, 152:3238 (1994)
16 Yednock, et al., Nature, 356:63 (1992)
17 Baron, et al., J. Exp. Med., 177:57 (1993)
18 van Dinther-Janssen, et al., J. Immunology, 147:4207 (1991)
19 van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52:672 (1993)
20 Elices, et al., J. Clin. Invest., 93:405 (1994)
21 Postigo, et al., J. Clin. Invest., 89:1445 (1991)
22 Paul, et al., Transpl. Proceed., 25:813 (1993)
23 Okarhara, et al., Can. Res., 54:3233 (1994)
24 Paavonen, et al., Int. J. Can., 58:298 (1994)
25 Schadendorf, et al., J. Path., 170:429 (1993)
26 Bao, et al., Diff., 52:239 (1993)
27 Lauri, et al., British J. Cancer, 68:862 (1993)
28 Kawaguchi, et al., Japanese J. Cancer Res., 83:1304 (1992)
29 Kogan, et al., U.S. Pat. No. 5,510,332, issued Apr. 23, 1996
30 International Patent Appl. Publication No. WO 96/01644
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
VLA-4 (also referred to as xcex14xcex21 integrin and CD49d/CD29), first identified by Hemler and Takada1 is a member of the xcex21 integrin family of cell surface receptors, each of which comprises two subunits, an xcex1 chain and a xcex2 chain. VLA-4 contains an xcex14 chain and a xcex21 chain. There are at least nine xcex21 integrins, all sharing the same xcex21 chain and each having a distinct xcex1 chain. These nine receptors all bind a different complement of the various cell matrix molecules, such as fibronectin, laminin, and collagen. VLA-4, for example, binds to fibronectin. VLA-4 also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on cytokine-activated human umbilical vein endothelial cells in culture. Distinct epitopes of VLA-4 are responsible for the fibronectin and VCAM-1 binding activities and each activity has been shown to be inhibited independently.2 
Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive for leukocytes. The mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection. For reviews of adhesion receptors of the immune system, see, for example, Springer3 and Osborn4.
Inflammatory brain disorders, such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium/leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue. Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases. The leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis.
In other organ systems, tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes. For example, it has been shown that the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to the injured tissue causing still further insult (Vedder et al.5). Other inflammatory or medical conditions mediated by an adhesion mechanism include, by way of example, asthma6-8, Alzheimer""s disease, atherosclerosis9-10, AIDS dementia11, diabetes12-14 (including acute juvenile onset diabetes), inflammatory bowel disease15 (including ulcerative colitis and Crohn""s disease), multiple sclerosis16-17, rheumatoid arthritis18-21, tissue transplantation22, tumor metastasis23-28, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
In view of the above, assays for determining the VLA-4 level in a biological sample containing VLA-4 would be useful, for example, to diagnosis VLA-4 mediated conditions. Additionally, despite these advances in the understanding of leukocyte adhesion, the art has only recently addressed the use of inhibitors of adhesion in the treatment of inflammatory brain diseases and other inflammatory conditions29,30. The present invention addresses these and other needs.
This invention provides compounds which bind to VLA-4. Such compounds can be used, for example, to assay for the presence of VLA-4 in a sample and in pharmaceutical compositions to inhibit cellular adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4. The compounds of this invention have a binding affinity to VLA-4 as expressed by an IC50 of about 15 xcexcM or less (as measured using the procedures described in Example A below).
Accordingly, in one of its composition aspects, this invention is directed to a compound of Formula (Ia) or (Ib): 
wherein:
Ar1 is an aryl, heteroaryl, cycloalkyl, or heterocyclic group wherein said aryl, heteroaryl, cycloalkyl, or heterocyclic group is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, xe2x80x94OS(O)2-alkyl, xe2x80x94OS(O)2-substituted alkyl, xe2x80x94OS(O)2-aryl, xe2x80x94OS(O)2-substituted aryl, xe2x80x94OS(O)2-heteroaryl, xe2x80x94OS(O)2-substituted heteroaryl, xe2x80x94OS(O)2-heterocyclic, xe2x80x94OS(O)2-substituted heterocyclic, xe2x80x94OSO2xe2x80x94NRR where each R is independently hydrogen or alkyl, xe2x80x94NRS(O)2-alkyl, xe2x80x94NRS(O)2-substituted alkyl, xe2x80x94NRS(O)2-aryl, xe2x80x94NRS(O)2-substituted aryl, xe2x80x94NRS(O)2-heteroaryl, xe2x80x94NRS(O)2-substituted heteroaryl, xe2x80x94NRS(O)2-heterocyclic, xe2x80x94NRS(O)2-substituted heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-alkyl, xe2x80x94NRS(O)2xe2x80x94NR-substituted alkyl, xe2x80x94NRS(O)2xe2x80x94NR-aryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted aryl, xe2x80x94NRS(O)2xe2x80x94NR- heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-substituted heteroaryl, xe2x80x94NRS(O)2xe2x80x94NR-heterocyclic, xe2x80x94NRS(O)2xe2x80x94NR-substituted heterocyclic where R is hydrogen or alkyl, xe2x80x94N[S(O)2xe2x80x94Rxe2x80x2]2 and xe2x80x94N[S(O)2xe2x80x94NRxe2x80x2]2 where each Rxe2x80x2 is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
Ar2 is an aryl or heteroaryl group optionally substituted, in addition to ring B or C, with one or two substituent(s) selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, substituted alkoxy, acyloxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, acylamino, aminoacyl, N-acyl-N-alkylamino, substituted N-acyl-N-alkylamino, (alkylsulfonyl)amino, substituted (alkylsulfonyl)amino, N-(alkylsulfonyl)-N-alkylamino, substituted N-(alkylsulfonyl)-N-alkylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, cyano, acyl, substituted acyl, carboxy, substituted carboxy, thiol, alkylthio, substituted alkylthio, alkylsulfoxy, substituted alkylsulfoxy, alkylsulfonyl, and substituted alkylsulfonyl;
Z is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
B is a group wherein W, together with xe2x80x94C(xe2x95x90Z)NR2xe2x80x94, forms a saturated or unsaturated heterocyclic group containing 2 to 5 carbon atoms and 0 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and xe2x80x94SOnxe2x80x94 (where n is 0 to 2) wherein said saturated or unsaturated heterocyclic group is optionally fused with one or two ring(s) structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group to form a bi- or tri-fused ring system and further wherein said heterocyclic group and each of such ring structures are optionally substituted with 1 to 3 substituents selected from the group consisting of with one or two substituent(s) selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, substituted alkoxy, acyloxy, substituted acyloxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, acylamino, substituted acylamino, N-acyl-N-alkylamino, substituted N-acyl-N-alkylamino, alkylene dioxy, (alkylsulfonyl)amino, substituted (alkylsulfonyl)amino, N-(alkylsulfonyl)-N-alkylamino, substituted N-(alkylsulfonyl)-N-alkylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, cyano, acyl, substituted acyl, carboxy, substituted carboxy, nitro, thiol, alkylthio, substituted alkylthio, alkylsulfoxy, substituted alkylsulfoxy, alkylsulfonyl, substituted alkylsulfonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R2 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;
C is a group wherein Wxe2x80x2, together with xe2x80x94C(xe2x95x90Z)Nxe2x80x94, forms a saturated or unsaturated heterocyclic group containing 2 to 5 carbon atoms and 0 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and xe2x80x94SOnxe2x80x94 (where n is 0 to 2) wherein said saturated or unsaturated heterocyclic group is optionally fused with one or two ring(s) structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group to form a bi- or tri-fused ring system and further wherein said heterocyclic group and each of such ring structures are optionally substituted with 1 to 3 substituents selected from the group consisting of with one or two substituent(s) selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, substituted alkoxy, alkylenedioxy, acyloxy, substituted acyloxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, acylamino, substituted acylamino, N-acyl-N-alkylamino, substituted N-acyl-N-alkylamino, (alkylsulfonyl)amino, substituted (alkylsulfonyl)amino, N-(alkylsulfonyl)-N-alkylamino, substituted N-(alkylsulfonyl)-N-alkylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, cyano, nitro, acyl, substituted acyl, carboxy, substituted carboxy, thiol, alkylthio, substituted alkylthio, alkylsulfoxy, substituted alkylsulfoxy, alkylsulfonyl, substituted alkylsulfonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and xe2x80x94NRxe2x80x3Rxe2x80x3 where each Rxe2x80x3 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
and enantiomers, diasteromers and pharmaceutically acceptable salts thereof;
and further wherein the compound of Formula I has a binding affinity to VLA-4 as expressed by an IC50 of about 15 xcexcM or less.
In a preferred embodiment, in compound (Ia), B is either:
(a) a group wherein W, together with xe2x80x94C(xe2x95x90Z)NR2xe2x80x94 where Z is xe2x80x94Oxe2x80x94, forms an unsaturated heterocyclic group containing 3 or 4 carbon atoms and 0 or 1 additional nitrogen atoms and further wherein the unsaturated heterocyclic group is optionally substituted, in addition to the R2 group, with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino. Preferably B is 2-pyridone, (e.g., 2-pyridon-3-yl, 2-pyridon-4-yl, etc.,) or 6-pyrimidone (e.g., 6-pyrimidon-5-yl, etc.,) that is optionally substituted, in addition to the R2 group, with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino, more preferably methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy (wherein the methyl, ethyl, propyl, butyl, and allyl group in said methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy may be optionally substituted with one, two or three substituents selected from the group consisting of hydroxy, alkoxy, thiol, alkylthio, alkylsulfoxide, alkylsulfone, halo, alkylamino, dialkylamino, amino, aminoacyl, preferably, hydroxy, methoxy, ethoxy, methylthio, methylsulfane, methylsulfone, fluoro, methylamino, dimethylamino, amino, and acetylamino), chloro, bromo, hydroxy, methylamino, or dimethylamino. More preferably in the above rings R2 is alkyl, preferably methyl; or
(b) a group wherein W, together with xe2x80x94C(xe2x95x90Z)NR2xe2x80x94 where Z is xe2x80x94Oxe2x80x94, forms a saturated or unsaturated heterocyclic group containing 3 or 4 carbon atoms and 0 or 1 additional nitrogen atoms wherein said saturated or unsaturated heterocyclic group is fused to a heterocyclic ring selected from the group consisting of dioxolane, dioxane, homodioxane, oxetane, tetrahydrofuran, dihydropyran, furan, oxazolidine, oxazole, isoxazole, oxazolidinone, oxathiolane, and 1,3-dioxolan-2-one and wherein the resulting fused ring is optionally substituted, in addition to the R2 group, on any ring atom capable of substitution with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino. Preferably B is 2-pyridone or 6-pyrimidone that is fused to a heterocyclic ring selected from the group consisting of dioxolane, dioxane, homodioxane, oxetane, tetrahydrofuran, dihydropyran, furan, oxazolidine, oxazole, isoxazole, oxazolidinone, oxathiolane, and 1,3-dioxolan-2-one, and wherein the resulting fused ring is optionally substituted, in addition to the R2 group, on any ring atom capable of substitution with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino, more preferably methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy (wherein the methyl, ethyl, propyl, butyl, and allyl group in said methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy may be optionally substituted with one, two or three substituents selected from the group consisting of hydroxy, alkoxy, thiol, alkylthio, alkylsulfoxide, alkylsulfone, halo, alkylamino, dialkylamino, amino, aminoacyl, preferably, hydroxy, methoxy, ethoxy, methylthio, methylsulfane, methylsulfone, fluoro, methylamino, dimethylamino, amino, and acetylamino), chloro, bromo, hydroxy, methylamino, or dimethylamino. More preferably in the above rings R2 is alkyl, preferably methyl.
In a preferred embodiment, in compound (Ib), C is either:
(a) a group wherein Wxe2x80x2, together with xe2x80x94C(xe2x95x90Z)Nxe2x80x94 where Z is xe2x80x94Oxe2x80x94, forms an unsaturated heterocyclic group containing 2 to 4 carbon atoms and 0 to 2 additional nitrogen atoms and further the wherein the unsaturated heterocyclic group is optionally substituted, in addition to the R2 group, with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino. Preferably C is 2-pyridon-1-yl or 6-pyrimidon-1-yl that is optionally substituted, in addition to the R2 group, with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino, more preferably methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy (wherein the methyl, ethyl, propyl, butyl, and allyl group in said methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy may be optionally substituted with one, two or three substituents selected from the group consisting of hydroxy, alkoxy, thiol, alkylthio, alkylsulfoxide, alkylsulfone, halo, alkylamino, dialkylamino, amino, aminoacyl, preferably, hydroxy, methoxy, ethoxy, methylthio, methylsulfane, methylsulfone, fluoro, methylamino, dimethylamino, amino, and acetylamino), chloro, bromo, hydroxy, methylamino, or dimethylamino. More preferably in the above rings R2 is alkyl, preferably methyl; or
(b) a group wherein Wxe2x80x2, together with xe2x80x94C(xe2x95x90Z)Nxe2x80x94 where Z is xe2x80x94Oxe2x80x94, forms a saturated or unsaturated heterocyclic group containing 2 to 4 carbon atoms and 0 to 2 additional nitrogen atoms wherein said saturated or unsaturated heterocyclic group is fused to a heterocyclic ring selected from the group consisting of dioxolane, dioxane, homodioxane, oxetane, tetrahydrofuran, dihydropyran, furan, oxazolidine, oxazole, isoxazole, oxazolidinone, oxathiolane, and 1,3-dioxolan-2-one and wherein the resulting fused ring is optionally substituted, in addition to the R2 group, on any ring atom capable of substitution with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino. Preferably C is 2-pyridon-1-yl or 6-pyrimidon-1-yl that is fused to a heterocyclic ring selected from the group consisting of dioxolane, dioxane, homodioxane, oxetane, tetrahydrofuran, dihydropyran, furan, oxazolidine, oxazole, isoxazole, oxazolidinone, oxathiolane, and 1,3-dioxolan-2-one, and wherein the resulting fused ring is optionally substituted, in addition to the R2 group, on any ring atom capable of substitution with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino, more preferably methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy (wherein the methyl, ethyl, propyl, butyl, and allyl group in said methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy may be optionally substituted with one, two or three substituents selected from the group consisting of hydroxy, alkoxy, thiol, alkylthio, alkylsulfoxide, alkylsulfone, halo, alkylamino, dialkylamino, amino, aminoacyl, preferably, hydroxy, methoxy, ethoxy, methylthio, methylsulfane, methylsulfone, fluoro, methylamino, dimethylamino, amino, and acetylamino), chloro, bromo, hydroxy, methylamino, or dimethylamino. More preferably in the above rings R2 is alkyl, preferably methyl.
In another preferred embodiment, Ar1 in compounds (Ia) and (Ib) is a heteroaryl group optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen, preferably 1-oxo-1,2,5-thiadiazole, 1,1-dioxo-1,2,5-thiadiazole, 1,3,5-triazine, pyridazine, pyrimidine or pyrazine substituted with above substituents; more preferably pyridazine, pyrimidine or pyrazine wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
In yet another preferred embodiment, Ar2 in compounds (Ia) and (Ib) is phenyl.
In the above preferred embodiments, a more preferred group of compounds is that wherein X is hydroxyl and R1 is hydrogen.
In yet another preferred embodiment, this invention is directed to compounds of formula IIa, IIb, IIc, IId, or IIe: 
wherein
X is hydroxyl or alkoxy;
Ar2 is an aryl or heteroaryl group optionally substituted, in addition to ring B, with one or two substituent(s) selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, substituted alkoxy, acyloxy, substituted acyloxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, acylamino, substituted acylamino, N-acyl-N-alkylamino, substituted N-acyl-N-alkylamino, (alkylsulfonyl)amino, substituted (alkylsulfonyl)amino, N-(alkylsulfonyl)-N-alkylamino, substituted N-(alkylsulfonyl)-N-alkylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, cyano, acyl, substituted acyl, carboxy, substituted carboxy, thiol, alkylthio, substituted alkylthio, alkylsulfoxy, substituted alkylsulfoxy, alkylsulfonyl, and substituted alkylsulfonyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and xe2x80x94SO2R10 where R10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R16 and R17 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and
R18 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R20 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R21 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
b is 1 or 2; and
B is a group wherein W, together with xe2x80x94C(xe2x95x90Z)NR2xe2x80x94, forms a saturated or unsaturated heterocyclic group containing 2 to 5 carbon atoms and 0 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and xe2x80x94SOnxe2x80x94 (where n is 0 to 2) wherein said saturated or unsaturated heterocyclic group is optionally fused with one or two ring(s) structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group to form a bi- or tri-fused ring system and further wherein said heterocyclic group and each of such ring structures are optionally substituted with 1 to 3 substituents selected from the group consisting of with one or two substituent(s) selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, substituted alkoxy, acyloxy, substituted acyloxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, acylamino, substituted acylamino, N-acyl-N-alkylamino, substituted N-acyl-N-alkylamino, alkylene dioxy, (alkylsulfonyl)amino, substituted (alkylsulfonyl)amino, N-(alkylsulfonyl)-N-alkylamino, substituted N-(alkylsulfonyl)-N-alkylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, cyano, acyl, substituted acyl, carboxy, substituted carboxy, nitro, thiol, alkylthio, substituted alkylthio, alkylsulfoxy, substituted alkylsulfoxy, alkylsulfonyl, substituted alkylsulfonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R2 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl; and
and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
Preferably, the compound is selected from formula IIc, IId or IIe.
In the above compounds II(a-e), B is either:
(a) a group wherein W, together with xe2x80x94C(xe2x95x90Z)NR2xe2x80x94 where Z is xe2x80x94Oxe2x80x94, forms an unsaturated heterocyclic group containing 2 to 4 carbon atoms and 0 to 2 additional nitrogen atoms and further the wherein the unsaturated heterocyclic group is optionally substituted, in addition to the R2 group, with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino. Preferably B is 2-pyridone, (e.g., 2-pyridon-3-yl, 2-pyridon-4-yl, etc.,) or 6-pyrimidone (e.g., 6-pyrimidon-5-yl, etc.,) that is optionally substituted, in addition to the R2 group, with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino, more preferably methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy (wherein the methyl, ethyl, propyl, butyl, and allyl group in said methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy may be optionally substituted with one, two or three substituents selected from the group consisting of hydroxy, alkoxy, thiol, alkylthio, alkylsulfoxide, alkylsulfone, halo, alkylamino, dialkylamino, amino, aminoacyl, preferably, hydroxy, methoxy, ethoxy, methylthio, methylsulfane, methylsulfone, fluoro, methylamino, dimethylamino, amino, and acetylamino), chloro, bromo, hydroxy, methylamino, or dimethylamino. More preferably in the above rings R2 is alkyl, preferably methyl; or
(b) a group wherein W, together with xe2x80x94C(xe2x95x90Z)NR2xe2x80x94 where Z is xe2x80x94Oxe2x80x94, forms a saturated or unsaturated heterocyclic group containing 2 to 4 carbon atoms and 0 to 2 additional nitrogen atoms wherein said saturated or unsaturated heterocyclic group is fused to a heterocyclic ring selected from the group consisting of dioxolane, dioxane, homodioxane, oxetane, tetrahydrofuran, dihydropyran, furan, oxazolidine, oxazole, isoxazole, oxazolidinone, oxathiolane, and 1,3-dioxolan-2-one and wherein the resulting fused ring is optionally substituted, in addition to the R2 group, on any ring atom capable of substitution with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino. Preferably B is 2-pyridone or 6-pyrimidone that is fused to a heterocyclic ring selected from the group consisting of dioxolane, dioxane, homodioxane, oxetane, tetrahydrofuran, dihydropyran, furan, oxazolidine, oxazole, isoxazole, oxazolidinone, oxathiolane, and 1,3-dioxolan-2-one, and wherein the resulting fused ring is optionally substituted, in addition to the R2 group, on any ring atom capable of substitution with 1 or 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, halo, hydroxy, mono or dialkylamino, preferably methyl, ethyl, propyl, methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy (wherein the methyl, ethyl, propyl, butyl, and allyl group in said methoxy, ethoxy, propoxy, butoxy, allyloxy, butenyloxy may be optionally substituted with one, two or three substituents selected from the group consisting of hydroxy, alkoxy, thiol, alkylthio, alkylsulfoxide, alkylsulfone, halo, alkylamino, dialkylamino, amino, aminoacyl, preferably, hydroxy, methoxy, ethoxy, methylthio, methylsulfane, methylsulfone, fluoro, methylamino, dimethylamino, amino, and acetylamino), chloro, bromo, hydroxy, methylamino, or dimethylamino. More preferably in the above rings R2 is alkyl, preferably methyl and X is hydroxyl.
In the above compounds II(a-e), Ar2 is preferably phenyl.
Within the above preferred groups of II(a-e), a more preferred group of compounds is that wherein R5 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl. Even more preferably R5 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, n-hexyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl, 2-(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4-(CH3C(O)NHxe2x80x94)phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, 1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4-[CH3SC(xe2x95x90NH)]phenyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1,3,4-thiadiazol-2-yl, 4-[H2NC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-yl, 4-(3xe2x80x2-dimethylamino-n-propoxy)-phenyl, and 1-methylpyrazol-4-yl;
R16 is substituted amino;
R16, R17 and/or R20 are hydrogen; and
R18 and/or R21 are alkyl, substituted alkyl, aryl, or substituted aryl.
In a second aspect, this invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds defined herein.
In a third aspect, this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of compounds defined herein.
In the above compounds, when X is other than xe2x80x94OH or pharmaceutical salts thereof, X is preferably a substituent which will convert (e.g., hydrolyze, metabolize, etc.) in vivo to a compound where X is xe2x80x94OH or a salt thereof. Accordingly, suitable X groups are any art recognized pharmaceutically acceptable groups which will hydrolyze or otherwise convert in vivo to a hydroxyl group or a salt thereof including, by way of example, esters (X is alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, alkenoxy, substituted alkenoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, and the like).
This invention also provides methods for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound of this invention under conditions wherein said compound binds to VLA-4.
The compounds and pharmaceutical compositions of this invention are useful for treating disease conditions mediated by VLA-4 or leucocyte adhesion. Such disease conditions include, by way of example, asthma, Alzheimer""s disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn""s disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
Other disease conditions include, but are not limited to, inflammatory conditions such as erythema nodosum, allergic conjunctivitis, optic neuritis, uveitis, allergic rhinitis, Ankylosing spondylitis, psoriatic arthritis, vasculitis, Reiter""s syndrome, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, dermatomyositis, Wegner""s granulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporal arteritis, pericarditis, myocarditis, congestive heart failure, polyarteritis nodosa, hypersensitivity syndromes, allergy, hypereosinophilic syndromes, Churg-Strauss syndrome, chronic obstructive pulmonary disease, hypersensitivity pneumonitis, chronic active hepatitis, interstitial cystitis, autoimmune endocrine failure, primary biliary cirrhosis, autoimmune aplastic anemia, chronic persistent hepatitis and thyroiditis.
In a preferred embodiment, the disease condition mediated by VLA-4is an inflammatory disease.
Preferred compounds of this invention include those set forth in the Table below:
and are named as follows:
N-(2-(N,N-diethylamino)-5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-methyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-ethyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-methyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-ethyl-4-methoxy-6-pyridon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2-methylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-methyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N N-diethylamino)-5-(2-methylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-ethyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2-methylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2-methylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2-methylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-methyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N, N-diethylamino)-5-(2-methylpropyl)pyrimidin-4-yl)-L-4 xe2x80x2-(1-ethyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2-methylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(2-methylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1-ethylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-methyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1-ethylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-ethyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N, N-diethylamino)-5-(1-ethylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1-ethylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1-ethylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-methyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1-ethylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-ethyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1-ethylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1-ethylpropyl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisoxazol-4-yl)pyrimidin-4-yl)-L-4-(1-methyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisoxazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-ethyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N, N-diethylamino)-5-(3,5-dimethylisoxazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisoxazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisoxazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-methyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N, N-diethylamino)-5-(3,5-dimethylisoxazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-ethyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisoxazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3 ,5-dimethylisoxazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1,3,5-trimethylpyrazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-methyl4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N, N-diethylamino)-5-(1,3,5-trimethylpyrazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-ethyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N, N-diethylamino)-5-(1,3,5-trimethylpyrazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1,3,5-trimethylpyrazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1,3,5-trimethylpyrazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-methyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1,3,5-trimethylpyrazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-ethyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1,3,5-trimethylpyrazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(1,3,5-trimethylpyrazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisothiazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-methyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisothiazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-ethyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisothiazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisothiazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-2-pyridon-3-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisothiazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-methyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N, N-diethylamino)-5-(3, 5-dimethylisothiazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-ethyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine;
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisothiazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-propyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine; and
N-(2-(N,N-diethylamino)-5-(3,5-dimethylisothiazol-4-yl)pyrimidin-4-yl)-L-4xe2x80x2-(1-isopropyl-4-methoxy-6-pyrimidon-5-yl)phenylalanine.